Methadone is a well-known, synthetic opioid that is widely used in alleviating chronic pain as well as in treatment of opioid addiction. Methadone, as commonly used, is a racemic mixture of D- and L-isomers. See e.g., Shimoyama et al., JPET, 283:648-652 (1997).
It is well-established that the L-isomer of methadone has μ-opioid activity as well as N-methyl-D-aspartate (NMDA) receptor antagonist activity. The L-isomer also possesses the ability to block re-uptake of noradrenaline and serotonin. Unlike the L-isomer, the D-isomer of methadone has weak μ-opioid activity but has NMDA receptor antagonist activity.
Shimoyama et al., 283(2): 648-52 (1997) showed that intrathecal D-methadone produced antinociception in a neuropathic pain model in rats where antinociception was not reversed by naloxone. Naloxone acts as an opioid antagonist and can be used to counter the effects of opioids by binding opioid receptors including the μ-opioid receptor. Failure of naloxone to reverse antinociception caused by D-methadone suggested that D-methadone has an NMDA-receptor antagonism mechanism of action rather than an opioid-receptor method of action. U.S. Pat. No. 6,008,258 relates to treatment of neuropathic pain with the D-isomer of methadone.
However, more recent studies question the mechanism and efficacy of D-methadone. Carpenter et al., European Journal of Pain 4(1): 19-26 (2000) showed that racemic methadone inhibited C-fiber evoked response similar to morphine. D-methadone showed weaker but similar inhibitory activity that was blocked by naloxone.
Chizh et al., Neurosci. Ltrs 296: 117-20 (2000) showed that antinociceptive activity of D-methadone in different pain models was blocked by naloxone, making NMDA antagonism an unlikely contributor to its mechanism of action. Lemberg et al., Anesthesia & Analgesia 102: 1768-74 (2006) revealed that in neuropathic pain L-methadone showed greater potency than other opioids, while D-methadone was inactive. Finally, Sotgiu et al., Pharm. Res. 60: 284-90 (2009) demonstrated that in a neuropathic pain model, naloxone blocked the majority of, but not all, nociception by a racemic mixture of methadone, suggesting involvement of both the μ-opioid receptor and NMDA receptor antagonism.
Methadone efficacy has been tested in a double-blind randomized controlled study by Morley et al., Palliative Med. 17(7):576-87 (2003). This study showed an analgesic effect of racemic methadone in neuropathic pain. By contrast, a small group of patients with neuropathic pain enrolled in a phase I study of D-methadone showed no analgesic response despite a high dose of D-methadone, as discussed in U.S. Patent Application No. 2014/0088155.
U.S. Pat. No. 6,897,242 provides for the use of a non-racemic methadone mixture for treatment of chronic pain.
The varying efficacy in treatment of pain reported for different methadone isomers and different types of pain as well as the prevalence of neuropathic pain reveal a need to attain more effective dosing of methadone isomers in order to best treat pain, such as for example neuropathic pain and mixed pain.
Back pain alone has a neuropathic component in 41-55% of cases, with more than 2 million cases of neuropathic back pain the United States. Currently available options for treatment of neuropathic back pain, such as for example tapentadol, D-methadone with another opioid, or racemic methadone, are inadequate and pose risks of side effects as well as risks of tolerance and addiction.
Drug compositions that increase safety and decrease risk of tolerance and side effects are desirable for the pain, such as neuropathic pain. The non-racemic mixtures of the D- and L-forms of methadone disclosed herein, compositions comprising such mixtures and methods of treatment using such mixtures and compositions unexpectedly provide such advantages.